The Potential to Immunocloak Renal Allografts

免疫斗篷同种异体肾移植的潜力

• 批准号: 8643038
• 负责人: Lauren Brasile
• 金额: $ 100万
• 依托单位: BREONICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-25 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643038
• 关键词: Acute; Adverse effects; Affect; Antibodies; Antigen Presentation; Apical; Attention; Biomedical Engineering; Blood Vessels; Blood capillaries; Caring; Chronic; Clinical; Clinical Trials; Collagen Type IV; Data; Development; Development Plans; Devices; Dose; Electron Microscopy; Evaluation; Fibronectins; Foundations; Funding; Future; Goals; Graft Rejection; Graft Survival; Human; Immune; Immune Cell Activation; Immune system; Immunologics; Immunosuppression; Immunosuppressive Agents; Integrins; Kidney; Laminin; Lead; Leukocytes; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Metabolic; Necrosis; Nephrotoxic; Opportunistic Infections; Organ; Outcome; Perfusion; Pharmaceutical Preparations; Phase; Program Development; Regimen; Renal Tissue; Renal function; Reperfusion Therapy; Reporting; Research; Risk; Severities; Small Business Innovation Research Grant; Structure; Structure of renal vein; Surface; Surgical Replantation; T-Cell Activation; Technology; Therapeutic; Time; Transplantation; Vascular Endothelial Cell; Work; allograft rejection; capillary; clinically relevant; delayed graft function; design; immunogenic; immunogenicity; improved; kidney allograft; nano; new technology; novel; phase 1 study; phase 2 study; pressure; prevent; product development; public health relevance; receptor; response

DESCRIPTION (provided by applicant): The focus of this project is a novel immunomodifying therapy that provides protection from early allograft rejection in the absence of the standard toxic systemic immunosuppressive drug regimens. This novel therapy is a nano-barrier membrane called NB-LVF4 consisting of a matrix made of laminin, vitrogen, fibronectin and type IV collagen. NB-LVF4 is applied to "immunocloak" the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the host immune system; without adversely affecting renal function. The result is an apical surface that is non-thrombogenic and non- immunogenic and significantly delays the onset of rejection 5-fold over untreated controls by preventing allo- recognition that normally occurs immediately upon reperfusion. A warm acellular Exsanguinous Metabolic Support (EMS) perfusion technology that is entering clinical trials is the platform used to apply NB-LVF4. The immunocloaking technology will be a follow-on product that can be applied to a kidney allograft during ex vivo EMS perfusion. If the results of our studies support our hypotheses and prove that: 1. the immunogenicity of renal allografts can be further reduced by trapping passenger leukocytes that migrate into the recirculating EMS perfusate to prevent reentry into the kidney, 2. the use of a concordant low-dose immunosuppressive drug monotherapy potentiates long-term graft survival, 3. the mechanisms of protection provided by NB-LVF4 are fully elucidated, along with an understanding of how it degrades over time along the vasculature and 4. a strategy for the organ-specific re-application of NB-LVF4 posttransplant to replace systemic drug regimens can be achieved, the NB-LVF4 technology will mark a new era in transplantation. It is envisioned that the ability to eliminate toxic systemic immunosuppressive drug regimens will lead to a paradigm shift where instead of daily immunosuppressive drug regimens it will become feasible to re-administer NB-LVF4 every three to four weeks. However, even if these goals are not fully achieved, NB-LVF4 will still be clinically relevant. The ability to use NB-LVF4 treatment to eliminate systemic immunosuppression during the early posttransplant period will be important to expanding the cadaveric kidney donor pool with warm ischemically damaged DCD kidneys. The acute tubule necrosis that is the result of ischemic damage leads to delayed graft function that in turn is associated with the risk of developing currently untreatable chronic rejection. By eliminating the need for systemic immunosuppressive drugs, that are in of themselves nephrotoxic, during the early posttransplant period of acute tubule necrosis the severity and duration of delayed graft function would be ameliorated. The consultants and collaborators involved in this project are internationally recognized experts in their respective field and their involvement in this project will significantly increase the likelihood of successfu outcomes.

描述(申请人提供)：本项目的重点是一种新的免疫调节疗法，在缺乏标准有毒的全身免疫抑制药物方案的情况下，提供对早期同种异体移植排斥反应的保护。这种新疗法是一种名为NB-LVF4的纳米屏障膜，由层粘连蛋白、维他命原、纤维连接蛋白和IV型胶原组成的基质组成。NB-LVF4通过覆盖供体血管内皮细胞和宿主免疫系统之间的接触点，在不影响肾功能的情况下，应用于肾脏血管内的管腔表面。其结果是形成了一个非血栓和非免疫原性的心尖表面，通过防止通常在再灌注后立即发生的同种异体识别，显著延迟了排斥反应的发生，比未经治疗的对照组延迟了5倍。一种正在进入临床试验的温脱细胞排血代谢支持(EMS)灌注技术是用于应用NB-LVF4的平台。免疫遮盖技术将是一种后续产品，可以在体外EMS灌流期间应用于同种异体肾移植。如果我们的研究结果支持我们的假说，并证明：1.通过捕获迁移到再循环EMS灌流液中的乘客白细胞以防止再次进入肾脏，可以进一步降低移植肾的免疫原性；2.使用协调的小剂量免疫抑制药物单一疗法可以增强移植物的长期存活；3.NB-LVF4提供的保护机制得到充分阐明，并了解它如何随着时间的推移在血管系统中降解；4.可以实现移植后重新应用NB-LVF4以取代全身用药方案的策略，NB-LVF4技术将标志着移植的新纪元。据设想，消除有毒的全身免疫抑制药物方案的能力将导致范式转变，取代每日免疫抑制药物方案，每三到四周重新给药一次NB-LVF4将成为可能。然而，即使这些目标没有完全实现，NB-LVF4仍将具有临床意义。使用NB-LVF4治疗的能力 在移植后早期消除全身性免疫抑制对于扩大具有热缺血损伤的DCD肾脏的身体肾脏供者池将是重要的。急性肾小管坏死是缺血损伤的结果，导致移植肾功能延迟，继而与发生目前无法治愈的慢性排斥反应的风险有关。在急性肾小管坏死的移植后早期，通过消除对自身具有肾毒性的全身性免疫抑制药物的需求，移植肾功能延迟的严重程度和持续时间将得到改善。参与该项目的顾问和合作者在各自领域都是国际公认的专家，他们参与该项目将大大增加取得成功的可能性。